The development of metastasis in cancer poses a major obstacle in the successful treatment of cancer. Most cancer deaths are caused by the development of metastases.
The search for proteins responsible for metastasis has implicated Ras homology gene family GTPase RhoC. Overexpression of RhoC has been suggested to play a role in the development of metastasis. Although a precise understanding of how RhoC exerts its metastatic effects remains elusive, it has been found to be overexpressed in many cancers including ovarian cancer, lung cancer and melanomas.
The process by which the mammalian immune system recognises and reacts to foreign or alien materials is a complex one. An important facet of the system is the T-cell response. This response requires that T cells recognise and interact with complexes of cell surface molecules referred to as human leukocyte antigens (HLA) constituting the human major histocompatibility complex (MHC), and peptides. The peptides are derived from larger molecules, which are processed by the antigen presenting cells, which in turn present the HLA/MHC molecule. The interaction of T cells and complexes of HLA/peptide is restricted, requiring a T cell that is specific for a particular combination of an HLA molecule and a peptide. If a specific T cell is not present, there is no T-cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present.
The mechanism by which T cells recognise cellular abnormalities has also been implicated in cancer. E.g. in WO92/20356, a family of genes is disclosed which are processed into peptides which, in turn, are expressed on cells surfaces, and can lead to lysis of the tumour cells by specific cytotoxic T ymphocytes (CTLs, CD8 cells). These genes are referred to as the MAGE family and are said to code for “tumour rejection antigen precursors” or “TRAP” molecules, and the peptides derived there from are referred to as “tumour rejection antigens” or “TRAs”.
In WO 94/05304, nonapeptides are disclosed which bind to the HLA-A1 molecule. This reference discloses that, given the known specificity of particular peptides for particular HLA molecules, one should expect a particular peptide to bind one HLA molecule, but not others. This is significant, as different individuals possess different HLA phenotypes. As a result, while identification of a particular peptide as being a partner for a specific HLA molecule has diagnostic and therapeutic ramifications, these are only relevant for individuals with that particular HLA phenotype.
Thus, it is well established that peptide epitopes derived from tumour associated antigens (TAAs) can be recognised as antigens by CTLs in the context of MHC molecules. However, although it is generally accepted that most if not all, tumours are antigenic, only a few are indeed immunogenic in the sense that tumour progression is readily controlled by the immune system.
To overcome this limitation, several immunotherapeutic studies have been initiated, e.g. vaccinations with TAA-derived peptides. For melanoma, the tumour for which the largest number of CTL-defined TAAs has been characterised, powerful CTL responses against antigens have been induced by vaccination and some patients experienced a complete remission of their disease. However, most of the peptide epitopes used in these vaccination trials are melanocyte specific, and these peptides cannot be applied for tumours of non-melanocyte origin. Furthermore, expression of these TAAs is heterogeneous among tumours from different patients and can even vary among metastases obtained from one patient. However, during the last couple of years a number of tumour specific peptide antigens, which are expressed in a number of different cancers, have been identified, i.e. HER-2, Muc-1 and telomerase.
During the past decade numerous clinical trials have shown the feasibility of peptide specific vaccination to induce anti-tumor T-cell responses in cancer patients. The clinical course of the patients, however, was in most cases not improved. This discrepancy has in numerous cases been explained by immune escape mechanisms of the tumour cells.
Like the other Rho GTPases, RhoC affect several aspects of growth control, and cytoskeletal organization in response to extracellular factors. More recent data suggests a more differential role in that RhoC has been shown to play an important role in metastasising cancer cells. Thus, several lines of evidence demonstrate a high expression of RhoC in cancer cells, and that the metastatic potential of cancer cells depends on expression of RhoC. Selective increased expression of RhoC has been described in metastatic cancers.